Our goal is to define immunohistochemical markers that will best type lung cancer for diagnosis, prognosis, and selection of therapy. Small cell lung cancer (SCLC), characterized by neuroendocrine (NE) features, is responsive to chemo- and radiotherapy. Some non-SCLC also express NE features. The hypothesis is that these tumors might be more responsive to cytotoxic treatment than other non-SCLC. A. Characterization of markers. In a retrospective study a comprehensive group of 113 lung cancers were tested for the immunohistochemical expression of 17 antigens using a sensitive avidin-biotin-peroxidase technique. Logistic regression analysis was used to separate tumors into the proper categories (SCLC and carcinoid tumors versus NSCLC) based on the immunohistochemical markers. As a result 95% of the tumors were correctly predicted using the cell counts and staining intensities of only six markers. The results suggested that 1) individual marker counts are not useful in tumor classification, 2) "specific" NE markers such as serotonin and neuropeptides bombesin, calcitonin, ACTH, vasopressin, neurotensin are not useful, 3) the best NE markers are a panel of "general" NE markers (Chromogranin A, Leu 7, NSE) which are present in NE cells throughout the body. B. Clinicopathologic correlation. This panel of "general" NE markers were applied to the non-SCLC cases on protocol 83-15 in our branch. There was a concordant expression of immunohistochemical NE markers with other biochemical tests used to characterized NE differentiation such as L-dopa decarboxylase activity. Although the numbers were small, the response rate to chemotherapy was 60% (3/5) in the patients whose tumors were positive for NE markers versus 20% (4/21) in those with negative NE markers. The significance of the project lies in the possible identification of prognostically important clinical subsets of lung cancer. Immunohistochemistry provides a highly effective and specific technique to achieve this goal.